IRBs aren't a barrier -- it's up to trialists and clinicians to push for them

In November, the cardiology community received a major shock when the ORBITA trial investigators reported that angioplasty in patients with stable angina yielded essentially the same results as a sham procedure. Click here to read MedPage Today's original article on ORBITA. In this follow-up, we examine the effect it's had on views of the placebo effect and the practicalities of sham-controlled studies.

The ORBITA trial earned a place in the halls of cardiology fame (or infamy, depending on one's view) when it reported that percutaneous coronary intervention (PCI) was no better than a sham procedure for stable angina.

But one of the key messages, observed by many, was not the clinical impact -- which it is sure to have -- but that sham procedures can, and perhaps should, be done in PCI trials.

Roxana Mehran, MD, of Mount Sinai School of Medicine, in New York City, while a critic of the trial, argued that the focus should be on "the importance of this trial, which was to show that a controlled, placebo procedure is actually possible when we are questioning the need for procedure."

As Larry Husten of CardioBrief wrote for MedPage Today, despite PCI having recently celebrated its 40th anniversary and being the cornerstone of interventional cardiology, it had "never been tested in a thoroughly rigorous manner. Along with many other device-related procedures, PCI is inherently difficult to assess in an objective fashion in clinical trials, because it is nearly impossible to eliminate the impact that knowledge of treatment assignment might have on both patients and physicians."

Perhaps the results when it finally was tested in such a manner shouldn't have been surprising, Kim Eagle, MD, of the University of Michigan in Ann Arbor, said in an interview.

"I think we learned the placebo effect is as big as we thought it was," he said. "I guess it shouldn't be too unexpected when we look back at some of the previous studies that included sham placebo: The SYMPLICITY trial that looked at renal denervation, boy, there was a powerful effect on blood pressure."

Peter Block, MD, of Emory University in Atlanta, also pointed to the Vineberg surgical procedure done in the late 1950s and 1960s. "Placebo effects are enormous. That's not a bad thing. If I wave two cat femurs above your head and you get better, that's pretty easy and it's a good way to make you feel better. I have no problem with that."

Implications for Trials

With such universal agreement that the placebo effect is playing a role in PCI, clinical trials gained a mandate to incorporate sham.

"Really I think this makes us begin to rethink many of our studies with types of intervention and can we design some of these studies with a sham control built in to account for some of the placebo effect that we might see," said Richard Chazal, MD, immediate-past president of the American College of Cardiology.

"I believe we should be pushing for additional studies to make certain we completely understand the implications of ORBITA," he added.

In a session at the American Heart Association meeting, 2 weeks after ORBITA was reported, Harlan Krumholz, MD, of Yale University, suggested a wide range of trials to verify ORBITA would be worthwhile given the gaps in understanding of who may gain real benefit from PCI. "The question is who is going to pay for it and how quickly can we do it," he said.

Some thought it was telling that ORBITA was done in the U.K.'s national health system. "Many in the United States think that this study perhaps couldn't have been done in the U.S.," said Chazal. "With results of ORBITA, I think there's better support for looking at this type of study."

Who's On First?

The implications may extent beyond PCI to a wider range of procedures and devices.

While there seems to be a move to perhaps lessening regulatory requirements in order to get devices FDA approved, Michelle O'Donoghue, MD, of Brigham and Women's Hospital in Boston, said at the AHA session, "I think ORBITA really makes us take another important look at that and think about the importance of having sham controls for at least some of the devices."

However, Robert Califf, MD, who preceded Gottlieb as commissioner, said at the AHA session, "As far as I know, the FDA is not opposed to sham procedures. It's really [that] this is an issue for the clinical community. You want to get the truth, and I'm afraid all too often the pocketbook is so alluring. You know, if you want the FDA to be the defense against practitioners who want to make a ton of money, we could pass laws that would make that happen. But it seems like this is a clinical community issue to me, this decision."

Chazal agreed that it might not be for the FDA to mandate, "but I believe at the very least IRBs may now look at this differently than they did before and may be more attuned to the need for that type of study and more accommodating in the ability to design such studies."

On the other hand, Darren McGuire, MD, a bioethicist and cardiology trialist at UT Southwestern Medical Center in Dallas, who has served on numerous IRBs and FDA panels, didn't see ORBITA as shifting the dial for sham control in IRB approval. He argued that IRBs have not been what's holding back sham-controlled trials in PCI.

"IRBs just eat what they're fed. They deal with research proposals one at a time," he told MedPage Today. "I don't know that ORBITA impacts that at all. Sham control is always a possibility with any IRB and any submission."

"I think the difficulty is not from a regulatory standpoint and not the hurdle of the IRB but to find physicians who believe that there is sufficient equipoise to have their patients enrolled in a sham-controlled trial," said McGuire.

Kenneth Mahaffey, MD, who has headed major cardiology trials and been on many IRBs at Duke University and now at Stanford University, agreed that change will have to come from the clinical community, with cardiologists designing trials and enrolling patients in them.

"From the IRB perspective, IRBs have been approving clinical trials and studies with sham procedures for decades," he said. "I think that people, based on ORBITA, are now going to reevaluate need for doing it ... We often underestimate true placebo effects and because of that didn't necessarily feel blinding [was] as important."

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